Modulation of the tumor microenvironment with probiotic therapies

用益生菌疗法调节肿瘤微环境

• 批准号: 10380671
• 负责人: Nicholas Arpaia
• 金额: $ 56.13万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-03 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380671
• 关键词: 4T1; Address; Adjuvant; Adverse effects; Anaerobic Bacteria; Antibiotics; Antibodies; Antigen Presentation; Antitumor Response; Automobile Driving; Bacteria; Bar Codes; Biodistribution; Blood Circulation; Bone Tissue; Breast Cancer Model; Breast Cancer cell line; CD47 gene; CTLA4 gene; Cells; Cessation of life; Clinical Trials; Combined Modality Therapy; Cytolysis; Cytotoxic T-Lymphocytes; Defect; Disease; Distant Metastasis; Dose; Engineered Probiotics; Engineering; Environment; Escherichia coli; Face; Future; Genetic; Genetic Transcription; Goals; Growth; Homing; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; In complete remission; Inflammatory; Injections; Intelligence; Interleukin-12; Intravenous; Kinetics; Knock-out; Lesion; Libraries; Lipopolysaccharides; Luciferases; Lymphoma; Malignant Neoplasms; Measurement; Mediating; Medicine; Metastatic Neoplasm to the Liver; Metastatic breast cancer; Modeling; Molecular; Monitor; Mus; Neoplasm Metastasis; Neutrophil Infiltration; Oral; Organ; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide/MHC Complex; Phagocytes; Primary Lesion; Primary Neoplasm; Probiotics; Production; Property; Reporting; Safety; Soft tissue sarcoma; Solid Neoplasm; Source; Specificity; Stains; Streptococcus; T cell response; T-Lymphocyte; Therapeutic; Toxic effect; Translations; Tropism; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Unresectable; Woman; Work; antigen-specific T cells; base; cancer immunotherapy; cancer therapy; chemotherapy; complement system; cytokine; delivery vehicle; density; design; host-microbe interactions; immunogenicity; improved; in vivo imaging system; innovation; knockout gene; malignant breast neoplasm; microbial; mortality; mouse model; mutant; nanobodies; neoantigens; novel; pre-clinical; preclinical development; prevent; probiotic therapy; programmed cell death ligand 1; programs; side effect; success; synthetic biology; systemic toxicity; targeted treatment; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

Recent advances in cancer immunotherapy have provided promising treatment options for patients with triple-negative breast cancer (TNBC). Despite overall success in treating these malignancies, immunotherapeutic approaches face a number of unique challenges: (1) dose limitation due to off-target side effects, (2) additive toxicity of combination therapies, (3) and relatively low immunogenicity of breast cancer. To overcome these limitations, this proposal seeks to engineer probiotic strains of bacteria that selectively colonize breast cancer and locally release immunotherapeutics. The ultimate goal is to elicit more robust and diversified antitumor T cell immunity and promote the clearance of colonized primary and metastatic breast cancer lesions and systemically growing breast cancer-derived foci. The accompanying project will first focus on deciphering mechanisms that define the intratumoral tropism of the probiotic strain E. coli Nissle 1917 (EcN) by using antibody-mediated depletion approaches and targeted genetic knockouts to pinpoint host immunological pathways that regulate tumor-specific growth. Using synthetic biology approaches, EcN will then be engineered to stably express and release checkpoint inhibitor nanobodies targeting CD47, PD-L1, and CTLA-4 locally inside of tumors. Pro-inflammatory cytokines will additionally be expressed to promote antigen presentation and enhance cytotoxic T cell responses. The primary innovations of this proposal are in the combined approach of both developing a better understanding of probiotic colonization of tumors, along with engineering probiotics as an immunotherapeutic delivery vector. Specifically, this approach has several advantages over current therapeutic strategies, including: (1) identification of novel EcN host strains and mechanistic understanding of their tumor colonization for further improvements in engineered therapies, (2) tumor-specific production of immunotherapeutics, (3) bacteria lysis that leads to effective release of novel immunotherapeutics and lipopolysaccharides (LPS) adjuvant, and (4) local delivery of novel immunotherapeutic combinations that are toxic to deliver systemically. This work seeks to overcome current limitations of immunotherapies, by providing a targeted vehicle to locally deliver immunotherapies that stimulate antitumor immunity while preventing systemic toxicity and mitigating immune-related adverse effects.

癌症免疫疗法的最新进展为三阴性患者提供了有希望的治疗选择 乳腺癌（TNBC）。尽管在治疗这些恶性肿瘤方面取得了总体成功，但免疫治疗方法 面临许多独特的挑战：（1）由于脱靶副作用导致的剂量限制，（2）附加毒性 （3）乳腺癌的免疫原性相对较低。为了克服这些限制， 该提案旨在设计能够选择性定殖乳腺癌和局部的益生菌菌株。 释放免疫治疗药物。最终目标是引发更强大和多样化的抗肿瘤T细胞免疫 促进定植的原发性和转移性乳腺癌病灶的清除和全身生长 乳腺癌源性病灶。随附的项目将首先关注定义定义的机制 使用抗体介导的耗竭方法研究益生菌菌株 E. coli Nissle 1917 (EcN) 的瘤内趋向性 并有针对性地进行基因敲除，以查明调节肿瘤特异性的宿主免疫途径 生长。使用合成生物学方法，EcN 将被设计为稳定表达和释放检查点 靶向肿瘤内局部 CD47、PD-L1 和 CTLA-4 的抑制剂纳米抗体。促炎细胞因子 还将表达以促进抗原呈递并增强细胞毒性 T 细胞反应。 该提案的主要创新在于将两者结合起来，以更好地理解 益生菌在肿瘤中的定植，以及将益生菌改造为免疫治疗递送载体。 具体来说，这种方法比目前的治疗策略有几个优点，包括：（1）识别 新型 EcN 宿主菌株及其肿瘤定植机制的了解，以进一步改进 在工程治疗中，(2) 肿瘤特异性免疫治疗药物的生产，(3) 细菌裂解导致 新型免疫疗法和脂多糖（LPS）佐剂的有效释放，以及（4）局部递送 全身给药具有毒性的新型免疫治疗组合。这项工作旨在克服当前 免疫疗法的局限性，通过提供有针对性的载体来局部提供刺激免疫疗法 抗肿瘤免疫力，同时防止全身毒性并减轻免疫相关的不良反应。